1. Field of the Invention
This invention relates to novel derivatives of alkyl, phenyl or benzyl 3-oxoandrost-4-ene-17 beta-thiocarboxylates and the corresponding androsta-1,4-dienes. More specifically, it relates to 16 alpha, 17 alpha-acetonides and 17 alpha-hydroxy-16-methyl compounds which are optionally substituted at the 6 alpha-position with fluoro or chloro and at the 9 alpha-position with fluoro, chloro or bromo, and are substituted at the 11-position with betahydroxy, beta-chloro (when there is a 9 alpha-chloro) or a keto. The 17 beta-thiocarboxylates are active anti-inflammatory agents in mammals. The invention further relates to pharmaceutically active compositions comprising a selected 17 beta-thiocarboxylate of the invention in combination with pharmaceutically acceptable excipient. This invention even further relates to a process for the preparation of these novel compounds.
2. Prior Art
Certain 3-oxoandrost-4-ene 17 beta-carboxylic acids which are substituted at the 9 position with chlorine or fluorine and at the 11 position with keto or hydroxy or chloro group are known. See for example U.S. Pat. Nos. 3,828,080 and 3,981,894 both assigned to Glaxo. It is also known that 3-oxoandrost-4-ene 17 beta-carboxylic acids may be substituted at both the 9 alpha and 6 alpha positions with fluoros. See for example U.S. Pat. No. 3,636,010.
It is also known from U.S. Pat. No. 3,989,686 to Phillips et al of Glaxo that steroids of formula (II) ##STR1## wherein
R.sup.1 is H or CH.sub.3 ;
R.sup.2 is H or CH.sub.3 ;
R.sup.3 is H or, when R.sup.2 is H, C.sub.1-6 alkoxy, C.sub.1-5 alkyl, thiocyanato or halogen;
R.sup.4 is H or CH.sub.3 ;
R.sup.5 is C.sub.1-6 alkyl optionally substituted by halo or NR.sup.6 R.sup.7, where R.sup.6 and R.sup.7 are the same or different C.sub.1-6 alkyl or R.sup.6 and R.sup.7 together with N are morpholino, thiamorpholine or morpholino substituted with C.sub.1-6 alkyl; and
the dotted line in the "A" ring represents an optional double bond at these positions. These compounds are useful as anesthetics.
Methyl 3 beta-acetoxyallothiolcholonate and methyl 3 beta-acetoxy-etiothiochol-5-enate are also known. See, e.g., Jerger et al, Helv. Chem. Acta. 29, 684-92 (1947).
A heretofore unknown series of 3-oxoandrost-4-ene 17 beta-thiocarboxylates and derivatives thereof has been discovered and is disclosed herein. The 17 beta-thiocarboxylates exhibit topical anti-inflammatory activity and few adverse side effects.